Metal-free oxidative fluorination of phenols with [18F]fluoride

Article abstract of DOI:10.1002/anie.201201502

The radiochemical synthesis of [¹⁸F]4-fluorophenols is based on phenol umpolung under oxidative conditions and direct nucleophilic fluorination with [¹⁸F]fluoride (see scheme, TBAF=tetra-n-butylammonium fluoride, TFA=trifluoroacetic acid). Readily available O-unprotected 4-tert-butyl phenols are used as precursors in this one-pot protocol. The reaction is completed in less than 30 minutes at room temperature and can be performed using standard or microfluidic technology. Copyright

Full text of DOI:10.1002/anie.201201502

Angewandte
Chemie
DOI: 10.1002/anie.201201502
Radiochemistry
Metal-Free Oxidative Fluorination of Phenols with [18F]Fluoride**
Zhanghua Gao, Yee Hwee Lim, Matthew Tredwell, Lei Li, Stefan Verhoog, Matthew Hopkinson,
Wojciech Kaluza, Thomas Lee Collier, Jan Passchier, Mickael Huiban, and
Vꢀronique Gouverneur*
Positron emission tomography (PET) is a molecular imaging
technique that captures functional or phenotypic changes
associated with pathology.[1] This research field is currently
fuelled by the need for conceptually new 18F-radiolabeling
methods to satisfy clinical demand.[2] 18F-labeled aryl deriv-
atives are highly sought after in the context of both drug and
radiotracer development because of their advantageous
metabolic profile for in vivo applications.[3] The most chal-
lenging targets are aryl precursors that are not amenable to
nucleophilic
aromatic
substitution
reactions
with
[18F]fluoride. Electrophilic fluorination is a logical strategy
to access electron-rich 18F-labeled aryl fluorides, but this
approach is not adopted preferentially, as 18F2 is difficult to
handle and produced in low specific activity in comparison
with [18F]fluoride.[2] Electrophilic [18F]N–F-type reagents of
tamed reactivity have been developed, but to date they do not
address the issue of specific activity.[4,5] The direct coupling of
electron-rich aromatic compounds with [18F]fluoride is a con-
ceptually attractive alternative strategy, but notoriously
difficult to implement. For reaction discovery, [18F]4-fluoro-
phenol[6] is possibly the most archetypical target, as it is
a versatile prosthetic group for the synthesis of complex
radiopharmaceuticals,[7] and this structural submotif is thus
featured in many tracers that are used clinically. Representa-
tive examples include [18F]l-6-fluoro-m-tyrosine[8] and [18F]-
(1R, 2S)-6-fluorometaraminol[9] (Scheme 1). Ideally, the radi-
osynthesis of [18F]fluorophenol from [18F]fluoride should be
fast (the half-life of 18F is 109.77 mins), convenient to imple-
ment, and include use of a readily accessible or commercially
Scheme 1. Importance of the [18F]4-fluorophenol motif for positron
emission tomography.
available precursor. A one-step (or one-pot) protocol as
simple as the one developed for [18F]fluorodeoxyglucose
would be ideal. The methods available to date for accessing
[18F]fluorophenol require two steps or more with cartridge
purification of intermediates.[6]
[*] Dr. Z. Gao, Dr. Y. H. Lim, Dr. M. Tredwell, Dr. L. Li, S. Verhoog,
Dr. M. Hopkinson, W. Kaluza, Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford OX1 3TA (UK)
Recently, Ritter reported the synthesis of a fluoride-
derived electrophilic fluorination reagent for the late stage
18F labeling of electron-neutral and electron-rich aromatic
compounds.[10] This chemistry features the coupling of two
organometallic species, the 18F-labeled reagent that is pre-
pared by mixing [18F]fluoride with a PdIV complex, and the
substrate, which is activated as a PdII aryl complex; a protocol
that corresponds to a net [18F]fluoride umpolung strategy.
Three representative electron-neutral and electron-rich 18F-
labeled aryl fluorides were made accessible using this strategy.
We reasoned that the coupling of phenol derivatives with
[18F]fluoride could arise from a complementary metal-free
approach, involving aryl umpolung instead. Such a reactivity
switch from a nucleophilic to an electrophilic entity can be
imposed on aromatic compounds, such as phenols, using an
E-mail: veronique.gouverneur@chem.ox.ac.uk
Dr. J. Passchier, Dr. M. Huiban
Imanova Ltd Burlington Danes Building Imperial College London
Hammersmith Hospital
Du Cane Road, London W12 0NN (UK)
Dr. T. L. Collier
Advion BioSystems, Inc.
10 Brown Road, Ithaca, NY 14850 (USA)
[**] The authors thank the EPSRC (to Z.G., M.T., M.H.), the CRUK (to
Z.G., M.T.), GSK (to M.H.), the A*STAR NSS Overseas Ph.D.
Scholarship (to Y.H.L.), the K. C. Wong Education Foundation (to
L.L.), and Advion BioSystems for generous funding, Dr. John M.
Brown FRS for discussions and Dr. Oscar Lozano for technical
assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201502.
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external oxidant.[11,12] Based on these principles,
[18F]fluorophenol could be accessed directly from phenol in
the presence of a [18F]fluoride source upon oxidative fluori-
nation/dearomatization, followed by rearomatization
(Scheme 2). The oxidative nucleophilic fluorination of phe-
was therefore critical to identify an alternative NCA fluoride
source that is competent for the planned oxidative fluorina-
tion. The use of CsF or TBAF·3H2O was not successful for the
conversion of 4-tert-butylphenol into 4-fluoro-4-tert-butyl-2,5-
cyclohexadien-1-one. However, when combined with TFA,
both CsF and TBAF·3H2O led to the formation of 4-fluoro-4-
tert-butyl-2,5-cyclohexadien-1-one (47% and 29% conver-
sion, respectively). This lead result prompted us to explore
the direct 18F fluorination of 4-tert-butylphenol from
[18F]fluoride as a route to [18F]4-fluorophenol. Several
possible complications intrinsic to 18F labeling had to be
considered. The [18F]fluoride source is the limiting reagent,
thus implying that the starting material and the oxidant are
present in large excess. This reverse stoichiometry with
respect to cold experimentation can facilitate undesired
processes, such as overoxidation of any in situ formed
[18F]4-fluorophenol.[20] The excess starting material could
also act as a competing nucleophile in preference to
[18F]fluoride. The validation of the oxidative fluorination
from [18F]fluoride, leading to [18F]4-fluorophenol, is presented
in Table 1. Three [18F]fluoride sources were reacted with 4-
Table 1: 18F Fluorination of 4-tert-butylphenol 1a.
Scheme 2. Fluorination of phenol and derivatives with [18F]fluoride.
nols is known from the majority of studies targeting mono- or
difluorocyclohexadienones.[13] Mechanistically, a hypovalent
phenyloxenium ion is more often proposed as the key
intermediate captured with fluoride.[14] In 2002, Langlois
and co-workers established that 4-tert-butylphenol can be
converted to 4-fluorophenol upon treatment with bis(trifluor-
oacetoxy)iodobenzene (PIFA) and Et3N·3HF.[15] This study
built on the previously reported oxidative fluorination of
aromatic compounds, including phenol derivatives.[16] Based
on these precedents, we were poised to examine the potential
of metal-free oxidative fluorination in the context of
18F radiochemistry.[17] Herein, we report the successful vali-
dation of the proposed aryl umpolung radiolabelling strategy
with a new method to access no-carrier-added (NCA) [18F]4-
fluorophenol from [18F]fluoride and 4-tert-butylphenol, a com-
mercially available precursor. The strategy, which is easy to
implement, is extended to variously substituted phenol
derivatives.
Our optimum protocol for the oxidative fluorination of 4-
tert-butylphenol 1a consists of its treatment with one equiv-
alent of phenyliodine diacetate (PIDA; 0.05m) and four
equivalents of HF·pyridine in CH2Cl2 at room temperature
for 15 minutes followed by treatment with neat trifluoroacetic
acid (TFA; until 10% v/v in CH2Cl2 is reached) at room
temperature for 10 minutes. Under these conditions, 4-
fluorophenol is isolated analytically pure in 35% yield
(50% yield determined by 19F NMR spectroscopy of the
crude material).[18] For transferring the method to 18F labeling,
use of [18F]poly(hydrogen fluoride)pyridinium is disfavored
(carrier-added synthesis), because this known 18F-labeled
reagent leads to a labeled product of low specific activity.[19] It
Entry
18FÀ source[a]
c(1a)
RCY [%][c]
n
1
2
3
4
5
6
7
A
B[b]
C
C
C
0.2m
0.2m
0.2m
0.05m
0.1m
0.2m
0.4m
8[d,e]
trace[d]
8[d,f]
3
1
3
3
3
3
3
26[g]
21[g]
C
C
21[g]
21[g]
[a] A=[18F]KF/Kryptofix 222, B=[18F]CsF, C=[18F]TBAF. [b] [18F]CsF is
not soluble in CH2Cl2. [c] Decay-corrected RCY. [d] Experiments per-
formed with same batch of [18F]fluoride (i.e., same day). [e] 38% Purity
determined by radio-HPLC analysis excluding [18F]fluoride. [f] 47% Purity
determined by radio-HPLC analysis excluding [18F]fluoride. [g] Experi-
ments performed with same batch of [18F]fluoride (i.e., same day).
n=number of experiments, TBAF=tetra-n-butylammonium fluoride.
tert-butylphenol and PIDA/TFA in CH2Cl2, [18F]KF/
Kryptofix 222,[18F]CsF, and [18F]TBAF. All reagents used in
combination with PIDA and TFA led to the formation of
[18F]-2a, but were not equally efficient (entries 1–3). Only
trace amount of [18F]-2a was observed with [18F]CsF. Both
[18F]KF/Kryptofix 222 and [18F]TBAF led to [18F]-2a with
a decay-corrected radiochemical yield (RCY) of around 8%,
but since [18F]TBAF typically led to a cleaner reaction
mixture, this reagent was used for further experimentation.
Because the concentration did not seem to have a significant
impact on the RCY, all reactions were subsequently per-
formed at a concentration of 0.2m (entries 4–7). This vali-
dation study established a suitable operating protocol for
18F radiolabeling. Cyclotron-produced NCA aqueous
[18F]fluoride (1–3 GBq) was adsorbed onto an anion-
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exchange cartridge and released with
a
solution of
HPLC and radio-TLC analyses, ranging from 11% to 32%.
Bu4NHCO3 in acetonitrile/water (v/v 4:1). The solution was
azeotropically dried with MeCN, the remaining MeCN was
evaporated, and the residue was solubilized in CH2Cl2. The
substrate 4-tert-butylphenol (40 mmol) was added at room
temperature to an aliquot of [18F]TBAF solution ( ꢀ 5–
50 MBq), followed by a freshly prepared solution of PIDA
(1 equiv) and TFA (4 equiv) in CH2Cl2. The reaction mixture
was stirred for 15 minutes, after which a supplement of TFA
was added. Radio-TLC and radio-HPLC analysis was per-
formed after 10 minutes. This protocol gave [18F]4-fluorophe-
nol in 21% decay-corrected RCY (n = 3).
With the optimal conditions at hand, the substrate scope
of the oxidative fluorination was investigated. Various 4-tert-
butyl substituted phenols 1a–h were subjected to labeling
with [18F]fluoride using the optimized protocols (Table 2). All
precursors 1a–h (except 1 f) were successfully 18F-labeled
with decay-corrected RCYs, which were evaluated by radio-
The radio-HPLC traces of crude material indicated that the
radiochemical purity was variable. This observation prompted
us to provide isolated decay-corrected RCYs of analytically
pure 18F-labeled phenols for all transformations. The isolated
yields (calculated from the starting [18F]TBAF activity)
ranged from 7% to 21%. The reaction tolerates various
ortho-positioned substituents, including methyl and tert-butyl,
as well as ketone and vinylogous ester functionalities. [18F]2-
Bromo-4-fluorophenol is within reach, a pleasing result as this
compound can be cross-coupled after fluorination. The
18F fluorination of 2,5-di-tert-butylphenol is para selective,
the tert-butyl group in ortho position remained intact under
the reaction conditions. The reaction tolerates meta substitu-
tion on the phenol, as shown with the preparation of 3-
methyl-4-fluorophenol [18F]-2h. The only substrate that is not
responsive to 18F labeling is 4-tert-butyl-2-phenyl-phenol 1 f,
an unexpected result since this compound was successfully
fluorinated in 37% yield under our optimized nonradiochem-
ical conditions.[18] Only trace amounts of [18F]-2 f and 18F-
labeled impurities in addition to unreacted [18F]fluoride could
be detected by radio-HPLC of the crude reaction mixture.
Pleasingly, compound [18F]-2g was obtained with a specific
activity of 420 GBqmmolÀ1.[18]
Table 2: Oxidative 18F fluorination of 1a–h with [18F]TBAF.
Entry Substrate
Product
RCY of
RCY of
[18F]-2a–h [18F]-2a–h
[%][a] (n)
[%][b]
We next examined the reactivity of [18F]4-fluoro-2-bro-
mophenol [18F]-2g for cross-coupling with phenylboronic
acid, because the direct oxidative 18F fluorination of 1 f was
unsuccessful as a route to [18F]-2 f. We optimized the Suzuki–
Miyaura cross-coupling of 2g in MeOH/H2O (v/v 1:1),
because [18F]-2g available in this solvent mixture after
semipreparative HPLC purification.[18] The phosphine-free
ligands 2-amino-4,6-dihydroxypyrimidine (L1) and 2-dime-
thylamino-4,6-dihydroxypyrimidine (L2) have been success-
fully used for various Suzuki–Miyaura[21] and Sonogashira[22]
couplings in aqueous medium for functionalization of pro-
teins, however these ligands have not been explored in the
context of 18F radiochemistry.[23] We were pleased to find that
the Pd(OAc)2/2L1 complex led to the desired cross-coupled
product [18F]-2 f in more than 95% yield after ten minutes at
708C. Reducing the time to five minutes was less satisfactory
and led to decreased RCY or recovered starting material.[18]
[Pd(OAc)2(L2)2] was superior for the reductive debromina-
tion of [18F]-2g, which was completed within five minutes at
708C in the presence of potassium formate. Compound [18F]-
2a was obtained in more than 95% decay-corrected RCYand
more than 95% radiochemical purity (Scheme 3).
The oxidative fluorination of 1a was investigated in
a commercially available microfluidic device (Advion Nano-
Tek), which provides well-controlled stoichiometry between
the precursor, the oxidant, and [18F]fluoride at set flow
rates.[24] The technology[24] is advantageous, because only
small quantities of reagents are necessary, thereby allowing
multiple reactions to be performed from a single production
of radioisotope. In a typical protocol, NCA [18F]fluoride ion in
[18O]water was first adsorbed onto a small MP-1 cartridge
(ORTG, TN), then released with a solution of Bu4NHCO3
(600 mL, 10 mgmLÀ1 in acetonitrile/water, v/v 4:1) into a 5 mL
V-vial. The solution was dried by six cycles of azeotropic
evaporation with acetonitrile at 1058C, and solubilized in
1
2
3
4
5
6
7
8
15 (5)
13 (20)
15 (8)
32 (5)
11 (6)
13 (8)
trace (4)
16 (11)
13 (7)
16 (15)
21 (22)
7 (12)
20 (33)
–
18 (22)
16 (23)
[a] Average decay-corrected RCY based on n experiments. [b] Decay-
corrected RCYof isolated products; numbers in brackets refer to the yield
of this experiment determined by radio-TLC analysis.
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react for a further 10minutes prior to radio-HPLC and radio-TLC
analysis.
a solution of 4-tert-butylphenol in CH2Cl2/(CH2Cl)2 (v/v 7:3;
0.2m, 500 mL). Solutions of [18F]TBAF/precursor and freshly
prepared PIDA/TFA (0.2m, 500 mL) in anhydrous
CH2Cl2/(CH2Cl)2 (v/v 7:3) were loaded into separate storage
loops of the microreactor apparatus. For optimization of
reaction conditions, 10–20 mL of solution from each loop was
infused into the coiled microreactor (length: 2 m; i.d.,
100 mm) at different flow rates and temperatures.[18] After
fluorination, TFA (20–25 mL) was added to the reactor output
at room temperature. Analysis was performed in the usual
manner by radio-TLC. Under optimized conditions (RT, flow
rate 15 mLminÀ1), [18F]4-fluorophenol was obtained in 18%
RCY (n = 2).
Received: February 23, 2012
Revised: April 5, 2012
Published online: May 25, 2012
Keywords: fluoride ions · fluorination · oxidation ·
.
phenol umpolung · radiochemistry
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(40 mL) with 70% HF·pyridine (4 equiv) and PIDA (1 equiv)
gave 4,4-difluoro-2-bromo-cyclohexadienone in 45% yield of
isolated product.
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[26] For a representative study on the correlation of the substituent
effect and the redox potential of phenols, see: F. G. Bordwell, J.-
P. Cheng, J. Am. Chem. Soc. 1991, 113, 1736 – 1743.
[18] For details, see the Supporting Information.
Angew. Chem. Int. Ed. 2012, 51, 6733 –6737
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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